Impaired Mitophagy and Protein Acetylation Levels in Fibroblasts from Parkinson's Disease Patients

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect

Experimental study on the effect of adaptive flaps on the aerodynamics of an Ahmed body

We perform an experimental study on the turbulent flow around a square-back Ahmed body of height, h, at varying Re=u∞h/ν∈[0.5,1]×105, where u∞ is the free-stream velocity and ν is the incoming flow kinematic viscosity, under different yaw angles β=(0∘,-5∘,-10∘), to analyze the use of rear flexibly hinged parallel plates as a control strategy to reduce the drag in a self-adaptive manner under changing flow conditions. The model implements rear parallel rigid flaps of depth d=0.5h, which are mounted with torsional joints through embedded flexible foils of calibrated thickness. This holding system restricts the motion of the plates to a rotary displacement, θ. The fluid-structure dynamics is characterized by the reduced velocity, defined as U∗=u∞/fnh, where fn is the natural frequency of rotary oscillations of the hinged plates, measured in free-decay tests of flaps. In fact, we have explored the range of reduced velocity, U∗=[0,65], varying u∞ and consequently Re. We perform force and pressure measurements to quantify the variations of the drag and the base pressure coefficients while laser displacement sensors are used to obtain the angular flaps motion. Results show that the hinged plates decrease the drag coefficient of the original body by nearly 4.4% for flow conditions aligned with the body axis. Under cross-flow conditions, their efficiency is even larger, attaining relative reductions drag of nearly 9.1% at β=-10∘ (13.5% in comparison with a body with fixed rigid plates of the same depth). Such variations are shown to be associated with a passive reconfiguration process of rear flaps. Additionally, hinged flaps are shown to interact with the reflectional-symmetry-breaking (RSB) modes, typically present in the wake of three-dimensional bodies. At aligned conditions, the interaction with the RSB modes is characterized by two regimes, in such a way that the hinged flaps manage to partially stabilize the RSB modes, and consequently to inhibit the bistable behavior at low values of U∗ (in a similar manner to rigid flaps), while at high values of U∗, they respond dynamically to switches between the opposite wake deflections of the RSB modes, deviating themselves accordingly

Técnicas continuas de depuración extrarrenal. ¿Precoces o tardías? ¿Cuál es el momento idóneo para su inicio?

The development of acute kidney injury (AKI) is a frequent problem in critical care units (ICUs), specifically in subpopulations admitted with a diagnosis of sepsis or septic shock. In the literature, the indications for the application of CRRT are clear (both of renal and extrarenal origin). However, it seems unclear in any previously published study the ideal time of the beginning of these techniques, nor the impact this has on morbidity and mortality. The objective of this clinical trial is to analyze whether there are differences in mortality between 2 patients groups with AKI and septic shock, depending on the early or late onset of CRRT. It is open (no masking), and may fall into measurement bias during the measurement of the data. The study groups were homogeneous and randomized. However, they do not specify the type of CRRT mode used. The sample size initially calculated according to the power conferred on the study was not finally reached. The measurements were objective. Nonetheless, they do not clarify why they designate the early CRRT as early in the first 12 hours after the development of AKI and late 48 hours later. Results: There are no mortality differences at 90 days (P = 0.38, not significant). It seems that in the late group 38% did not receive CRRT, and 17% received it early. The late group presented significantly fewer days with CRRT. There were no differences in days of mechanical ventilation, vasopressors or ICU stay.El desarrollo de insuficiencia renal aguda (IRA) constituye una problemática frecuente en las unidades de cuidados críticos (UCI), concretamente en las subpoblaciones ingresadas con diagnóstico de sepsis o shock séptico. En la literatura, las indicaciones de aplicación de TCRR están claras (tanto de origen renal como extrarrenal). Sin embargo, no parece claro en ningún estudio publicado previamente el momento ideal del inicio de dichas técnicas, ni la repercusión que esto tiene en la morbimortalidad. El objetivo de este ensayo clínico es analizar si existen diferencias en la mortalidad entre 2 grupos de pacientes con lesión renal aguda y shock séptico, según el inicio precoz o tardío de las TCRR. Es abierto (no hay enmascaramiento), pudiendo caer en sesgo de medición durante la medición de los datos. Los grupos de estudio fueron homogéneos, con aleatorización al azar. Sin embargo, no especifican el tipo de modalidad de TCRR utilizada. El tamaño muestral calculado inicialmente según la potencia conferida al estudio no fue alcanzado finalmente. Las mediciones fueron objetivas. Sin embargo, no aclaran por qué designan como precoz al inicio de las TCRR en las primeras 12 horas desde el desarrollo de LRA y tardío a 48 horas después. Resultados: No hay diferencias de mortalidad a los 90 días (P=0.38, no significativo). Sin embargo, en el grupo tardío un 38% no recibieron TCRR, y 17 % lo recibieron precozmente. El grupo tardío presentó de forma significativa menos días con TCRR. No hubo diferencias en días de ventilación mecánica, vasopresores ni estancia en UCI

Causes of Morbidity in Wild Raptor Populations Admitted at a Wildlife Rehabilitation Centre in Spain from 1995-2007: A Long Term Retrospective Study

Background: Morbidity studies complement the understanding of hazards to raptors by identifying natural or anthropogenic factors. Descriptive epidemiological studies of wildlife have become an important source of information about hazards to wildlife populations. On the other hand, data referenced to the overall wild population could provide a more accurate assessment of the potential impact of the morbidity/mortality causes in populations of wild birds. Methodology/Principal Findings: The present study described the morbidity causes of hospitalized wild raptors and their incidence in the wild populations, through a long term retrospective study conducted at a wildlife rehabilitation centre of Catalonia (1995-2007). Importantly, Seasonal Cumulative Incidences (SCI) were calculated considering estimations of the wild population in the region and trend analyses were applied among the different years. A total of 7021 birds were analysed: 7 species of Strigiformes (n = 3521) and 23 of Falconiformes (n = 3500). The main causes of morbidity were trauma (49.5%), mostly in the Falconiformes, and orphaned/young birds (32.2%) mainly in the Strigiformes. During wintering periods, the largest morbidity incidence was observed in Accipiter gentillis due to gunshot wounds and in Tyto alba due to vehicle trauma. Within the breeding season, Falco tinnunculus (orphaned/young category) and Bubo bubo (electrocution and metabolic disorders) represented the most affected species. Cases due to orphaned/young, infectious/parasitic diseases, electrocution and unknown trauma tended to increase among years. By contrast, cases by undetermined cause, vehicle trauma and captivity decreased throughout the study period. Interestingly, gunshot injuries remained constant during the study period. Conclusions/Significance: Frequencies of morbidity causes calculated as the proportion of each cause referred to the total number of admitted cases, allowed a qualitative assessment of hazards for the studied populations. However, cumulative incidences based on estimated wild raptor population provided a more accurate approach to the potential ecological impact of the morbidity causes in the wild populations

Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and Technology (CICYT), the Spanish National Parks agency, the European Commission, the Spanish Ministry of Science, and the European Social Fund

Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and Technology (CICYT), the Spanish National Parks agency, the European Commission, the Spanish Ministry of Science, and the European Social Fund

HLA-DRB1 association with Henoch-Schonlein purpura

Objective: Henoch-Schönlein purpura (HSP) is the most common vasculitis in children but it is not exceptional in adults. Increased familial occurrence supports a genetic predisposition for HSP. In this context, an association with the human leukocyte antigen-HLA-DRB1*01 phenotype has been suggested in Caucasian individuals with HSP. However, data on the potential association of HSP with HLA-DRB1*01 were based on small case series. To further investigate this issue, we performed HLA-DRB1 genotyping of the largest series of HSP patients ever assessed for genetic studies in Caucasians. Methods: 342 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al classification criteria, and 303 sex and ethnically matched controls were assessed. HLA-DRB1 alleles were determined using a PCR-Sequence-Specific-Oligonucleotide Probe (PCR-SSOP) method. Results: A statistically significant increase of HLA-DRB1*01 in HSP patients when compared with controls was found (43% vs 7%, respectively; p<0.001; odds ratio-OR=2.03 [1.43-2.87]). It was due to the increased frequency of HLA-DRB1*0103 phenotype in HSP (14% vs 2%; p<0.001; OR=8.27 [3.46-23.9]). These results remained statistically significant after adjusting for Bonferroni correction. In contrast, a statistically significant decreased frequency of the HLA-DRB1*0301 phenotype was observed in patients compared to controls (5.6% vs 18.1%, respectively; p<0.001, OR=0.26 [0.14-0.47]), even after adjustment for Bonferroni correction. No HLA-DRB1 association with specific features of the disease was found. Conclusion: Our study confirms an association of HSP with HLA-DRB1*01 in Caucasians. Also, a protective effect against the development of HSP appears to exist in Caucasians carrying the HLA-DRB1*03 phenotype

Evolution of Disease Response Genes in Loblolly Pine: Insights from Candidate Genes

BACKGROUND: Host-pathogen interactions that may lead to a competitive co-evolution of virulence and resistance mechanisms present an attractive system to study molecular evolution because strong, recent (or even current) selective pressure is expected at many genomic loci. However, it is unclear whether these selective forces would act to preserve existing diversity, promote novel diversity, or reduce linked neutral diversity during rapid fixation of advantageous alleles. In plants, the lack of adaptive immunity places a larger burden on genetic diversity to ensure survival of plant populations. This burden is even greater if the generation time of the plant is much longer than the generation time of the pathogen. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present nucleotide polymorphism and substitution data for 41 candidate genes from the long-lived forest tree loblolly pine, selected primarily for their prospective influences on host-pathogen interactions. This dataset is analyzed together with 15 drought-tolerance and 13 wood-quality genes from previous studies. A wide range of neutrality tests were performed and tested against expectations from realistic demographic models. CONCLUSIONS/SIGNIFICANCE: Collectively, our analyses found that axr (auxin response factor), caf1 (chromatin assembly factor) and gatabp1 (gata binding protein 1) candidate genes carry patterns consistent with directional selection and erd3 (early response to drought 3) displays patterns suggestive of a selective sweep, both of which are consistent with the arm-race model of disease response evolution. Furthermore, we have identified patterns consistent with diversifying selection at erf1-like (ethylene responsive factor 1), ccoaoemt (caffeoyl-CoA-O-methyltransferase), cyp450-like (cytochrome p450-like) and pr4.3 (pathogen response 4.3), expected under the trench-warfare evolution model. Finally, a drought-tolerance candidate related to the plant cell wall, lp5, displayed patterns consistent with balancing selection. In conclusion, both arms-race and trench-warfare models seem compatible with patterns of polymorphism found in different disease-response candidate genes, indicating a mixed strategy of disease tolerance evolution for loblolly pine, a major tree crop in southeastern United States

Radiographers supporting radiologists in the interpretation of screening mammography: a viable strategy to meet the shortage in the number of radiologists.

BackgroundAn alternative approach to the traditional model of radiologists interpreting screening mammography is necessary due to the shortage of radiologists to interpret screening mammograms in many countries.MethodsWe evaluated the performance of 15 Mexican radiographers, also known as radiologic technologists, in the interpretation of screening mammography after a 6 months training period in a screening setting. Fifteen radiographers received 6 months standardized training with radiologists in the interpretation of screening mammography using the Breast Imaging Reporting and Data System (BI-RADS) system. A challenging test set of 110 cases developed by the Breast Cancer Surveillance Consortium was used to evaluate their performance. We estimated sensitivity, specificity, false positive rates, likelihood ratio of a positive test (LR+) and the area under the subject-specific Receiver Operating Characteristic (ROC) curve (AUC) for diagnostic accuracy. A mathematical model simulating the consequences in costs and performance of two hypothetical scenarios compared to the status quo in which a radiologist reads all screening mammograms was also performed.ResultsRadiographer's sensitivity was comparable to the sensitivity scores achieved by U.S. radiologists who took the test but their false-positive rate was higher. Median sensitivity was 73.3 % (Interquartile range, IQR: 46.7-86.7 %) and the median false positive rate was 49.5 % (IQR: 34.7-57.9 %). The median LR+ was 1.4 (IQR: 1.3-1.7 %) and the median AUC was 0.6 (IQR: 0.6-0.7). A scenario in which a radiographer reads all mammograms first, and a radiologist reads only those that were difficult for the radiographer, was more cost-effective than a scenario in which either the radiographer or radiologist reads all mammograms.ConclusionsGiven the comparable sensitivity achieved by Mexican radiographers and U.S. radiologists on a test set, screening mammography interpretation by radiographers appears to be a possible adjunct to radiologists in countries with shortages of radiologists. Further studies are required to assess the effectiveness of different training programs in order to obtain acceptable screening accuracy, as well as the best approaches for the use of non-physician readers to interpret screening mammography